Preparation of thiazole derivatives

ABSTRACT

A process for the preparation of a thiazole derivative of the formula ##STR1## where R 1  to R 4  are organic radicals and R 3  and R 4  may also be hydrogen, by reacting a compound of the formula ##STR2## with a methylene-active compound of the formula ##STR3## in the presence of a base, and the thiazole derivative thus obtained.

This application is a continuation-in-part of application Ser. No. 001,832 filed Jan. 8, 1980, now abandoned.

The present invention relates to a process for the preparation of tautomeric compounds of the general formulae IA and IB ##STR4## where

R¹ and R² are cyano, formyl, nitro, unsubstituted or substituted alkanoyl or aroyl, a carboxylic acid ester group, unsubstituted or substituted carbamyl or sulfamyl, alkylsulfonyl, arylsulfonyl or alkylsulfinyl,

R¹ and R² may also together be a cyclic radical and

R² may also be aryl or hetaryl,

R³ and R⁴ are hydrogen, unsubstituted or substituted alkyl, aryl, hetaryl, a carboxylic acid ester group, alkanoyl or aroyl and

R³ and R⁴ may also together be a cyclic radical, wherein a compound of the formula II ##STR5## is reacted with a compound of the formula III ##STR6## in the presence of a base.

The invention also relates to novel thiazoles.

Examples of radicals R¹ and R² are C₁ -C₈ -alkanoyl, which is unsubstituted or substituted by, for example, chlorine, bromine or C₁ -C₄ -alkoxy, benzoyl which is unsubstituted or substituted by chlorine, bromine, methyl, ethyl, methoxy, ethoxy or cyano, naphthoyl, carboxylic acid ester groups derived from C₁ -C₈ -alkanols, C₂ - to C₈ -glycols or -glycol ethers or phenols, carbamoyl or sulfamoyl substituted by C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyalkyl, cyclohexyl or phenyl, C_(1-C) ₄ -alkylsulfonyl or C₁ -C₈ -alkylsulfinyl, phenylsulfonyl or phenylsulfinyl.

The same radicals may be mentioned as examples of R³ and R⁴ within the scope of the general definition.

Specific examples of radicals R¹, in addition to those already mentioned, are: COCH₃, COC₂ H₅, COC₃ H₇, COCH₂ Cl, COCHCl₂, COC₆ H₅, COC₆ H₄ Cl, COOCH₃, COOC₂ H₅, COOC₃ H₇, COOC₄ H₉, COOC₆ H₅, COO(CH₂)₃ OCH₃, COO(CH₂)₃ OC₂ H₅, CONHCH₃, CONHC₂ H₅, CONHC₃ H₇, CONHC₄ H₉, CON(CH₃)₂, CON(C₂ H₅)₂, CONH₂, CONHC₆ H₅, ##STR7## as well as the corresponding sulfamoyl radicals, CH₃ SO₂, C₂ H₅ SO₂, C₄ H₉ SO₂ and CH₃ SO.

R² may be identical with R¹, and in addition some specific examples of R² are O₂ N-C₆ H₄, NC-C₆ H₄, CH₃ COC₆ H₄, ##STR8##

R¹ and R² together may also form a cyclic radical, for example ##STR9## where aryl is phenyl which is unsubstituted or substituted by, for example, chlorine, bromine, methyl, ethyl, methoxy or ethoxy.

Specific examples of radicals R³ and R⁴ are:

CH₃, C₂ H₅, C₃ H₇, C₄ H₉, C₅ H₁₁, C₆ H₅, C₆ H₁₃, C₇ H₁₅, C₁ - bis C₄ -alkyl-OC₆ H₄, (C₁ -C₄ -alkyl)₂ OC₆ H₃, Cl-C₆ H₄ Cl₂ C₆ H₃, BrC₆ H₄, Br₂ C₆ H₃, C₁ -C₄ -alkyl- S-C₆ H₄, H₅ C₆ S-C₆ H₄, C₁ -C₄ -alkyl-CONHC₆ H₄, COOCH₃, COOC₂ H₅, COOC₃ H₇, COOC₄ H₉, COC₆ H₅, COCH₃ and CH₂ COO-C₁ -C₄ -alkyl,

R³ and R⁴ together can also complete a ring, for example ##STR10##

Suitable bases for the reaction are, in principle, all basic compounds, eg. alkali metal compounds or alkaline earth metal compounds, amines and alcoholates.

Specific examples are hydroxides, eg. NaOH, KOH, Ca(OH)₂, Ba(OH)₂ and Mg(OH)₂, carbonates, eg. Na₂ CO₃, K₂ CO₃ and Li₂ CO₃, alcoholates, eg. NaOCH₃, NaOC₂ H₅, KOH(CH₃)₃ and KOCH₃, and amines, eg. NH₃, ethylamine, piperidine, pyrrolidine, N(CH₃)₃, N(C₂ H₅)₃, N(C₄ H₉)₃, N(CH₂ CH₂ OH)₃, C₆ H₅ N(CH₃)₂ and pyridine.

The reaction of the compounds II and III is advantageously carried out in a solvent. Examples of suitable solvents are hydrocarbons, alcohols, glycols, glycol ethers, amides, ethers, ketones and nitriles; the solvents may also be used as mixtures with water.

In some cases, the bases may also serve as solvents.

Specific examples of solvents are toluene, xylenes, chlorobenzene, methylene chloride, ethylene chloride, chloroform, methanol, ethanol, isopropanol, isobutanol, ethylene glycol, ethylene glycol monomethyl ether, monoethyl ether and monobutyl ether, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, cyclohexanone, acetonitrile and dimethylsulfoxide.

Examples of preferred solvents are methanol, ethanol, isobutanol and dimethylformamide.

Details of how the reaction may be carried out are to be found in the Examples, where parts and percentages are by weight, unless stated otherwise.

The process according to the invention is of particular importance for the preparation of compounds of the formula Ia ##STR11## where

B¹ and B² are cyano, C₁ -C₄ -alkoxycarbonyl, C₁ -C₄ -alkanoyl, substituted carbamoyl or hetaryl and

B³ and B⁴ are unsubstituted or chlorine-, bromine-, C₁ -C₄ -alkoxy-, methyl-, acetylamino- or C₁ -C₄ -alkylmercapto-substituted phenyl, methyl or ethyl.

The compounds of the formula I are valuable intermediates, e.g. for the preparation of dyes, and many of them are novel.

Specific examples of dyes obtainable with the compounds of formula I are e.g. described in copending Application Ser. No. 920,638, now 4,239,894.

The invention hence also concerns, by way of novel products, the compounds of the formula IV ##STR12## where

X¹ is cyano, nitro, unsubstituted or substituted carbamoyl or sulfamoyl, alkylsulfonyl, arylsulfonyl or alkylsulfinyl,

X² is cyano, nitro, unsubstituted or substituted carbamoyl or sulfamoyl, alkylsulfonyl or alkylsulfinyl, a carboxylic acid ester group, aryl or hetaryl, and

X¹ and X² may also, together with the methine group, be a cyclic radical and

R³ and R⁴ have the stated meanings.

EXAMPLE 1 4-Phenyl-thiazolylmalodinitrile

33 parts of malodinitrile and 90 parts of phenacyl thiocyanate are introduced into 500 parts of alcohol. 46 parts of triethylamine are then added dropwise at 30° C., whilst stirring, after which the reaction mixture is stirred at room temperature overnight. It is then diluted with 500 parts of H₂ O and is rendered slightly acid with glacial acetic acid, and the product is filtered off; it is a finely crystalline powder. Yield: 112 parts=99.5%.

Melting point 255° C. (with decomposition).

EXAMPLE 2 Methyl 4-phenylthiazolylcyanoacetate

90 parts of phenacyl thiocyanate are introduced into a mixture of 150 parts of DMF, 150 parts of triethylamine and 50 parts of methyl cyanoacetate. The mixture is then stirred for 4 hours at room temperature, after which it is introduced into water and the batch is acidified with acetic acid. The product which precipitates is filtered off and dried in an oven.

Yield: 129 parts=93%, melting point 176° C.

EXAMPLE 3 4-Phenyl-thiazolylmalodinitrile

The procedure followed is as described in Example 1, except that instead of triethylamine 43 parts of piperidine are employed.

Yield: 112 g.

EXAMPLE 4 4-Phenyl-thiazolylmalodinitrile

The procedure followed is as described in Example 1, except that instead of triethylamine 30 parts of 30% strength ammonia are employed.

Yield 68%.

EXAMPLE 5 4-Phenyl-thiazolylmalodinitrile

The procedure followed is as described in Example 1, except that instead of triethylamine 143 parts of sodium carbonate dissolved in a little water are added.

Yield: 91%.

EXAMPLE 6 4-Phenyl-thiazolylmalodinitrile

The procedure followed is as described in Example 1, but instead of alcohol 600 parts of toluene are used. The product is isolated by distilling off the solvent.

Yield: 46%.

EXAMPLE 7 4-Methylthiazolylmalodinitrile

33 parts of malodinitrile are introduced into 400 parts of methanol; 57 parts of thiocyanatoacetone are added, followed by 50 parts of triethylamine added whilst cooling. The reaction mixture is stirred for 4 hours at room temperature and is then introduced into water, the batch is acidified with formic acid and the product is filtered off.

Yield: 71 parts=88%.

EXAMPLE 8 Methyl 4-methylthiazolylcyanoacetate

50 parts of methyl cyanoacetate, 50 parts of triethylamine and 57 parts of thiacyanoatoacetone are reacted in 400 parts of methanol as described in Example 7.

Yield: 79 parts=70%; melting point 235° C.

EXAMPLE 9

14.3 parts of 1-thiacyanato-diethyl ketone are reacted with 6.6 parts of malodinitrile as described in Example 1.

Yield: 12.4 parts; melting point 225° C.

EXAMPLE 10 4-Ethoxycarbonylmethylthiazolylmalodinitrile

19 parts of ethyl γ-thiocyanato-acetoacetate are reacted with 6.6 parts of malodinitrile as described in Example 1.

Yield: 21 parts.

EXAMPLE 11 Tetrahydrobenzthiazolylmalodinitrile

15.4 parts of 1-thiocyanatocyclohexanone are reacted with 6.6 parts of malodinitrile as described in Example 1.

Yield: 14.3 parts.

EXAMPLE 12 Methyl tetrahydrobenzthiazolyl-cyanoacetate

The procedure described in Example 11 is followed, but instead of malodinitrile 10 parts of methyl cyanoacetate are employed.

Yield: 16 parts.

Compounds 13 to 34 are prepared by methods similar to the instructions given in Example 1.

    ______________________________________                                         Example                                                                               Compound                  Yield                                         ______________________________________                                         13                                                                                     ##STR13##                85%                                           14                                                                                     ##STR14##                83%                                           15                                                                                     ##STR15##                80%                                           16                                                                                     ##STR16##                95%                                           17                                                                                     ##STR17##                93%                                           18                                                                                     ##STR18##                70%                                           19                                                                                     ##STR19##                73%                                           20                                                                                     ##STR20##                89%                                           21                                                                                     ##STR21##                86%                                           22                                                                                     ##STR22##                80%                                           23                                                                                     ##STR23##                83%                                           24                                                                                     ##STR24##                82%                                           25                                                                                     ##STR25##                83%                                           26                                                                                     ##STR26##                90%                                           -27                                                                                    ##STR27##                95%                                           28                                                                                     ##STR28##                84%                                           29                                                                                     ##STR29##                83%                                           30                                                                                     ##STR30##                60%                                           31                                                                                     ##STR31##                55%                                           32                                                                                     ##STR32##                51%                                           33                                                                                     ##STR33##                80%                                           34                                                                                     ##STR34##                60%                                           ______________________________________                                    

EXAMPLE 35

18 parts of phenacyl thiocyanate, 10 parts of triethylamine and 16 parts of N,N-dimethylbarbituric acid in 100 parts of propanol are refluxed for 2 hours. The mixture is then cooled and the product filtered off. 10 parts of the compound of the formula ##STR35## are obtained.

Compounds 36 to 38 are prepared similarly.

    ______________________________________                                         Example    Compound                                                            ______________________________________                                         36                                                                                         ##STR36##                                                          37                                                                                         ##STR37##                                                          38                                                                                         ##STR38##                                                          ______________________________________                                     

I claim:
 1. A process for the preparation of a thiazole derivative of the general formula ##STR39## where R¹ and R² are cyano; formyl; nitro; C₁ -C₈ alkanoyl, which is unsubstituted or substituted by chlorine, bromine or C₁ -C₄ -alkoxy; benzoyl which is unsubstituted or substituted by chlorine, bromine, methyl, ethyl, methoxy, ethoxy or cyano; naphthoyl; carboxylic acid ester groups derived from C₁ -C₈ -alkanols, C₂ - to C₈ -glycols, C₂ -C₈ -glycol ethers or phenols; carbamyl or sulfamoyl which is unsubstituted or substituted by C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyalkyl, cyclohexyl or phenyl; C₁ -C₄ -alkylsulfonyl; C₁ -C₈ -alkylsulfinyl; phenylsulfonyl or phenylsulfinyl;R¹ and R² may also together be a cyclic radical selected from the group consisting of ##STR40## where aryl is phenyl which is unsubstituted or substituted by chlorine, bromine, methyl, ethyl, methoxy or ethoxy; and R² may also be O₂ N--C₆ H₄, NC--C₆ H₄, CH₃ COC₆ H₄, ##STR41## R³ and R⁴ are hydrogen, CH₃, C₂ H₅, C₃ H₇, C₄ H₉, C₅ H₁₁, C₆ H₅, C₆ H₁₃, C₇ H₁₅, C₁ -bis C₄ -alkyl-OC₆ H₄, (C₁ -C₄ -alkyl)₂ OC₆ H₃, Cl-C₆ H₄ CL₂ C₆ H₃, BrC₆ H₄, Br₂ C₆ H₃, C₁ -C₄ -alkyl-S-C₆ H₄, H₅ C₆ S-C₆ H₄, C₁ -C₄ -alkyl-CONHC₆ H₄, COOCH₃, COOC₂ H₅, COOC₃ H₇, COOC₄ H₉, COC₆ H₅, COCH₃ or CH₂ -COO-C₁ -C₄ -alkyl; and R³ and R⁴ may also together be a cyclic radical selected from the group consisting of ##STR42## wherein a compound of the formula II ##STR43## is reacted with a compound of the formula III ##STR44## in the presence of a base selected from the group consisting of alkali metal compounds, alkaline earth metal compounds and amines.
 2. The process as claimed in claim 1, wherein R¹ and R² are CN, CHO, NO₂, COCH₃, COC₂ H₅, COC₃ H₇, COCH₂ CL, COCHCl₂, COC₆ H₅, COC₆ H₄ Cl, COOCH₃, COOC₂ H₅, COOC₃ H₇, COOC₄ H₉, COOC₆ H₅, COO(CH₂)₃ OCH₃, COO(CH₂)₃ OC₂ H₅, CONHCH₃, CONHC₂ H₅, CONHC₃ H₇, CONHC₄ H₉, CON(CH₃)₂, CON(C₂ H₅)₂, CONH₂, CONHC₆ H₅, ##STR45##
 3. The process as claimed in claim 1, wherein said base is selected from the group consisting of NaOH, KOH, Ca(OH)₂, Ba(OH)₂, Mg(OH)₂, Na₂ CO₃, K₂ CO₃, Li₂ CO₃, NaOCH₃, NaOC₂ H₅, KOC(CH₃)₃, KOCH₃, NH₃, ethylamine, piperidine, pyrrolidine, N(CH₃)₃, N(C₂ H₅)₃, N(C₄ H₉)₃, N(CH₂ CH₂ OH)₃, C₆ H₅ N(CH₃)₂ and pyridine.
 4. The process as claimed in claim 1, wherein a compound of the formula ##STR46## where B¹ and B² are cyano; C₁ -C₄ -alkoxy-carbonyl; C₁ -C₄ -alkanoyl; or carbamoyl substituted by C₁ -C₈ -alkyl, C₁ -C₈ -alkoxyalkyl, cyclohexyl or phenyl; andB³ and B⁴ are unsubstituted or chlorine-, bromine-, C₁₋₄ -alkoxy-, methyl-, acetylamino- or C₁ -C₄ -alkylmercapto-substituted phenyl, methyl or ethyl,is prepared. 